tbuckley/cabot-search huggingface dataset:
P12.15.A THE IMPACT OF MICROGLIA MODULATION ON THE IMMUNE TUMOR MICROENVIRONMENT IN SYNGENEIC GLIOBLASTOMA MOUSE MODELS
Authors: D Kaymak, T Shekarian, M Ritz, N Ferrari, R Kälin, R Glass, G Hutter
Journal: Neuro-Oncology (2023)

Abstract BACKGROUND Glioblastoma is exceptionally resistant to T-cell targeting immunotherapies for which the immunosuppressive myeloid compartment is held responsible. As influencer and instructor of antitumoral T-cell-immunity this compartment mainly consists of Monocyte-derived Cells (MdCs) and tissue-resident (TR) macrophages called microglia (MG). Since the response to immunotherapies depend on antigen presenting cells at the tumor site, we aim to investigate this compartment and its individual role in tumor progression by genetically depleting/activating the TR MG. METHODS We made use of two MG-specific and tamoxifen inducible knockout mouse models in which 1) we activate MG by excision of the activation-repressing transcription factor Sall1 (Sall1CreERT2/wt x Sall1fl/wt) and 2) deplete MG by deleting the “survival-receptor” Csf1r on MG (Sall1CreERT2/wt x Csf1rfl/fl). To investigate the effect of MG activation and depletion on the immune tumor microenvironment (iTME), immunocompetent mice were engrafted with syngeneic glioma cells (CT-2A, GL261) and the iTME subsequently characterized by scRNAseq, spectral flow cytometry and immunofluorescence imaging. RESULTS Upon Sall1-KO MG demonstrate a morphologically reactive phenotype reminiscent of activated MG. The MG-specific deletion of Csf1r effectively depletes the brain parenchyma of TR MG which rapidly gets repopulated by a morphologically distinct microglia-(like) population. Genetic activation of MG leads to a survival benefit in Gl261-engrafted mice compared to Cre-negative littermates. In contrast, depletion of MG significantly reduces the survival in Gl261 and CT-2A engrafted mice. ScRNAseq confirms the effective depletion of MG and the subsequent emergence of a microglia-like cell population that despite microscopical resemblance to MG, transcriptionally remains distinct. The iTME in MG-depleted mice is characterized by a decreased abundance of exhausted and naïve CD8-Tcells and an increased infiltration of MdCs. Gene set enrichment analysis demonstrate a dampened inflammatory immune profile of infiltrating MdCs highlighted by a downregulation of hallmark gene sets of “interferon-α and γ response” and “TNFα-signaling via NF-κB”. CONCLUSION The presence of MG orchestrate the development towards a more antitumorigenic iTME by shaping the antitumoral response of incoming myeloid cells and furthermore directly or indirectly influencing T-cell immunity. Understanding this interplay of MG and MdCs in cancer and its impact on instruction of antitumoral T-cell immunity could help guiding the development of novel immunotherapeutic strategies in GBM.
P15.06.A HYBRID [18F]FET PET-MRI; A VALUABLE ADVANCED IMAGING TOOL TO DISCRIMINATE BETWEEN TUMOR RECURRENCE AND PSEUDOPROGRESSION IN GLIOMA PATIENTS
Authors: J de Jong, I J Pruis, R Valkema, M J van den Bent, S E M Veldhuijzen van Zanten
Journal: Neuro-Oncology (2023)

Abstract BACKGROUND One of the well-known challenges in the response assessment of glioma patients is differentiating tumor recurrence from treatment-related effects, i.e. pseudoprogression. The PET tracer O-(2-18F-fluoroethyl)-L-tyrosine ([18F]FET) visualizes increased amino acid metabolism and can potentially aid differentiation between vital tumor tissue and reactive changes, and can herewith guide clinical decision-making and surgical planning. This study aimed to assess the diagnostic yield of hybrid [18F]FET PET-MRI in a series of pre-treated patients suspected of glioma recurrence. MATERIAL AND METHODS This retrospective study included histologically-confirmed glioma patients who had undergone standard-of-care therapy consisting of gross-total resection surgery and/or radiotherapy. [18F]FET PET-MRI scans were performed between 04/2022 and 03/2023. Patient received 204 MBq (median, range: 180-242) [18F]FET intravenously, followed directly by a 45 minute dynamic PET and simultaneous MRI including DWI and gadolinium-based sequences (PWI). Time-activity-curves (TACs), showing the mean tissue radioactivity in tumor regions of interest as a function of time, were compared to the TAC in healthy tissue. Static PET images for qualitative visual analysis were reconstructed by accumulating the 20-40 minute timeframes. Tumor recurrence (i.e., a positive scan) was defined as focal uptake exceeding uptake in healthy brain parenchyma according to the joint EANM/EANO/RANO practice guideline/SNMMI procedure standard. Outcomes were compared to previously-obtained MRIs, post-operative pathology, and clinical/radiological follow-up. RESULTS Thirteen patients, 31% female, median age 39 (range: 28-50), with astrocytoma (grade 2_n=2; grade 3_n=1; grade 4_n=2), oligodendroglioma (grade 2_n=6; grade 3_n=1), and glioblastoma (n=1) were included. [18F]FET PET-MRI was positive in 9/13 patients (70%), which in 5/9 (55%) was confirmed by pathology (n=3) or clinical follow-up (n=2). In 6/9 patients with a positive scan (66%), the previously-obtained MRI (time interval range: 0.5-4.1 months) showed negative (n=4) or unclear (n=2) DWI and PWI findings. Four/13 (30%) patients had a negative [18F]FET PET-MRI and did not show signs of tumor progression after an average follow-up of 3, 5, 11 and 12 months, respectively. CONCLUSION Simultaneous [18F]FET PET-MRI shows high potential for accurate differentiation between true tumor progression and treatment-related pseudoprogression in glioma patients with equivocal findings on MRI including DWI and PWI. The diagnostic yield of this hybrid imaging technique exceeded that of MRI-only in our case series, and thus provides a promising advanced imaging tool in the follow-up of glioma patients. We aim at prospective studies to validate the clinical value of this multimodal approach.
JS07.4.A REGIONAL B-CELL MEDIATED IMMUNOSUPPRESSION IDENTIFIED THROUGH SPATIAL AND SINGLE-CELL TRANSCRIPTOMIC ANALYSIS OF CHORDOMA
Authors: J Kada Benotmane, V A Arrieta, J Zhao, D Hou, J Katz, S Pandey, M Cholak, A Sonabend, C Horbinski, J Miska, R Stupp, M Lesniak, D Heiland, C Chang
Journal: Neuro-Oncology (2023)

Abstract BACKGROUND Chordomas, rare indolent neoplasms, mainly occur in the skull base or lower spine. Therapies, including surgery and radiotherapy, often fail to impede local recurrence. Though checkpoint inhibition therapy shows promise, recent immunotherapy trials failed to reach endpoints. Here, we aim to investigate the immunological landscape of chordomas using spatial and single-cell transcriptomics, and TCR/BCR profiling, elucidating cellular interplay and the intricate mechanisms governing the immunosuppressive tumor microenvironment. MATERIAL AND METHODS We generated a comprehensive single-cell atlas of the chordoma neoplastic landscape and its associated microenvironment, incorporating paired single-cell transcriptomic samples from blood and tumor cells of six patients, as well as single-cell BCR and TCR sequencing data. Utilizing scGEN, we integrated pre-annotated gene expression datasets and identified both established and novel antigen binding patterns by employing TCR Bidirectional Encoder Representations from Transformers (BERT). Moreover, we conducted GeoMx Digital Spatial Profiler (DSP) analysis by selecting regions of interest (ROIs) that encompass critical immunological and malignant niches. We also curated and quantified cell distributions in immunohistochemical staining for a total of 107 chordomas. RESULTS Utilizing pseudo-temporal mapping, we delineated the trajectories of CD8 and CD4 T cells in chordomas, spanning from blood to tumor stroma and encompassing naïve, memory, cytotoxic, and T cell exhaustion profiles. Through an integrated TCR profiling methodology, we observed extratumoral clonal expansion of cytotoxic and memory T cells in the blood, whereas the majority of intratumoral T cells with shared motifs exhibited terminal exhaustion. Leveraging TCR-BERT, we identified binding patterns exclusively enriched in exhausted T cell receptors' binding sites and uncovered shared motifs within the reactive tumor-infiltrating compartment, implying the existence of potential reservoirs for anti-tumor immunity. Investigating the cell-cell interactions driving intratumoral exhaustion, we identified M2 tumor-associated macrophages and a plasma cell phenotype-like subset upregulating TGFB and IL10 expression, referred to as regulatory B cells (Bregs). Spatial profiling substantiated the proximity of regulatory B cells and exhausted T cells within immunosuppressive niches, suggesting an underexplored mechanism contributing to tumor-derived T cell exhaustion. CONCLUSION Regulatory B-cells have been identified in the TME of various solid tumors, including colorectal, breast, cervical, and ovarian carcinomas. Our study emphasizes the role of regulatory B cells in the chordoma immune environment, providing crucial insights into novel immunosuppressive mechanisms and pathways leading to T cell exhaustion in chordoma.
P02.25.A THE IMPACT OF PSEUDOPROGRESSION IN OVERALL SURVIVAL IN GLIOBLASTOMA, EXPERIENCE IN OUR CENTER
Authors: E Iruarrizaga Ovejas, E Iza Rodríguez, J Mañe, E Novo Sukia, R Fernandez
Journal: Neuro-Oncology (2023)

Abstract BACKGROUND After surgery, standard treatment for glioblastoma (GBM) is temozolomide (TMZ), initially concurrent with radiotherapy (Ct-Rt), and subsequently as maintenance therapy. For adequate tumour response assessment,, magnetic resonance imaging (MRI) is performed one month after completing Ct-Rt. Instead, the radiologic images obtained in that MRI can be difficult to interpret because they may show radiation-induced pseudoprogression (psPD) rather than disease progression. METHODS We analyzed retrospectively clinical and tumor biology characteristics of patients (pts) with GBM treated in our center with Ct-Rt +/- adjuvant Qt and their relationship with psPD (reported by RANO criteria) and impact in overall survival (OS) RESULTS From November-2016 to October-2022, we collected data for 82 pts (median age: 60 years) who underwent Qt-Rt exclusively (25 patients) or Qt-Rt and adjuvant temozolomide (57 patients). Pts characteristics were: male/female 61.4/38.6%, performance status (PS) 0/1/2 10.5/71,9/17.5%, total surgery/subtotal/biopsy 21.1 / 52.6 / 26.3%, MGMT methylated/ not methylated/not realized 52.7/ 45.6 /1.8 %, TERT mutated/not mutated/not realized 29.8 / 7 / 36.8 / 63.2 %, ATRX positive/negative/not realized 75.4 / 14 / 10.5 %, P53: positive/negative 25 / 75 %. After Ct-Rt, MRI for evaluation of response showed: no evidence of disease 13.4%, partial response 4.9%, stable disease 34.1%, progressive disease 18.3% and psPD 26.8%. In multivariate analysis, significant difference of OS were observed in function of type of surgery (better OS in R0; p=0.015), performance status (better OS in PS 0-1; P=0.006), MGMT methylation (better OS in methylated; p=0.037), and ATRX status (better OS in negative; p=0.05). OS was algo significantly increased in pts treated with Qt-Rt and adjuvant Qt (17.7 +/- 1.7 months) vs Qt-Rt exclusively (11.35 +/-1.62 months) (p=0.013). In pts with psPD, OS was significantly superior compared with pts with progressive disease after Qt-Rt treatment (16.6 vs 11.3 months, p=0.048). In our cohort no differences between MGMT methylation status and psPD were observed (MGMT methylated 54.5%/ 45.5 not methylated). CONCLUSION It is essential to differenciate between PsPD and PD because it may have a clinical impact on chemotherapy-based treatment and OS, but it is also neccesary to know patient characteristics and tumor biology in order to identify patients that will beneficiate from TMZ. &amp;lt;!--EndFragment--&amp;gt;
JS03.5.A CLINICALLY COLLECTED VARIABLES FAIL TO RELIABLY PREDICT COGNITIVE FUNCTIONING IN UNTREATED GLIOMA PATIENTS
Authors: S M Boelders, G J M Rutten, K Gehring, L L Ong, E O Postma
Journal: Neuro-Oncology (2023)

Abstract BACKGROUND Previous research has identified several clinically collected variables (e.g., age and WHO grade) that are significantly related to impairments in cognitive functions before surgery in patients with a glioma. The degree to which clinically collected variables can collectively explain differences in cognitive functioning between patients, however, remains unclear, as most studies did not evaluate the total amount of variability between patients explained by a set of predictors. Furthermore, only linear or rank-based methods with a small number of variables have been used. In this study, we used various machine learning models to quantify the amount of variability in cognitive functioning we can explain using a comprehensive set of variables as identified from the literature that were collected as part of clinical care. The extent to which cognitive functioning can be reliably predicted reveals the degree to which these variables can explain individual differences between patients. MATERIAL AND METHODS We trained 11 machine learning models to predict pre-surgical cognitive function in patients with a glioma (n=354) across eight cognitive tests. Included variables comprised sociodemographics, tumor characteristics, medication, presenting symptoms, ASA score, comorbidities, and anxiety and depression scores. Model performance was evaluated on four objectives 1) predicting impairment on at least one cognitive test, 2) predicting the number of tests on which a patient is impaired, 3) predicting impairment for each test separately, and 4) predicting cognitive function for each test separately. Model performance, hyperparameter selection, and feature importance were analyzed and clinical implications were discussed. RESULTS Best-performing models demonstrated above-random performance for most objectives. Performance, however, was unreliable with poor predictions for a substantial number of patients on most objectives. Best-performing models were relatively simple and used most variables for prediction while not relying strongly on any specific variable. CONCLUSION Our results show that the clinically collected variables included in this study fail to reliably predict cognitive functioning. This indicates that these variables are unable to explain a considerable amount of variability between patients, despite many of these variables being significantly related to cognitive function in previous studies. Our results suggest that a multi-parametric (i.e., more holistic) view of an individual patient may be necessary to explain differences in cognitive functioning, ideally considering imaging markers, biological markers, sociodemographics, and clinical characteristics. Finally, our results stress the need to collect larger cross-center and multimodal datasets to better explain and predict individual differences in cognitive function.
P17.18.B RADIOTHERAPY IN GLIOBLASTOMA MULTIFORME COULD BE PLANNED WITH MARGINS LESS THAN 2 CM WITH LESS THAN 1 CM FROM THE SURGICAL BED
Authors: l H Oñoro Guzman.
Journal: Neuro-Oncology (2023)

Abstract BACKGROUND The administration of radiotherapy (Rt) plus adjuvant temozolamide (TMZ) with IMR and VMAT techniques has become an increasingly valuable tool in the local control of glioblastoma multiforme with a survival current Rt techniques allow specific conformation with the use of better radiological images that allow us greater precision. For many years large Rt field sizes have been associated with significant adverse effects.Although we continue to give very wide margins that lead us to irradiate non-compromised organs at risk, which translates into a higher rate of radionecrosis and acute and chronic neurological toxicity.Therefore, we consider it valid to ask ourselves if we could reduce the standard margins applied in the planning of Rt. MATERIAL AND METHODS Analysis of 98 GBM patients treatedat the barros luco hospital between 2021 and 2023 with surgery followed by adjuvant therapy, radiotherapy plus concomitant chemotherapy at the Institute. Nacional de Cáncer de Santiago de Chile we reviewed the time of recurrence and the location in relation to the surgical margins vs. radiotherapy margins or other nearby areas. RESULTS After the analysis, we can see that 65% of the recurrences presented a dominant failure pattern, within the field and less than 1cm from the margin between the surgical bed and the radiotherapy margin, evaluated with perfusion brain resonance imaging and spectroscopy CONCLUSION n the local control of GBM, the application of adjuvant therapy is essential in a period of not less than 2 months after surgery, in this institutional analysis we can observe a considerable number of patients under 40 years of age with this pathology, for which reason to consider reducing the diameter of Rt margins can be considered an option, in order to limit deleterious effects in healthy organs in the times that there are advanced Rt techniques, the increasingly frequent application of brain radiosurgery (SRS) thatIt can be used as a rescue method in case of recurrences at the edge of the margin, using radiological images (MRI with perfusion and spectroscopy/C-methionine PET/CT. Figure we can see the CTV and PTV to be treated with modulated intensity technique, evidencing the large field size that receives radiation between 54 to 60 Gy.Radiation oncology must continue to develop and improve the delivery, targeting, and dose of radiation therapy in the GBM to improve its survival and treatment-associated toxicity.
P09.05.A IMPACT OF A 16-WEEK SUPERVISED EXERCISE INTERVENTION ON CANCER-RELATED FATIGUE IN PATIENTS WITH NEWLY DIAGNOSED GLIOBLASTOMA UNDERGOING ADJUVANT CHEMOTHERAPY
Authors: J Jost, M S Kloss, R Brandt, K Völker, W Stummer, R G Wiewrodt, D Wiewrodt
Journal: Neuro-Oncology (2023)

Abstract BACKGROUND Cancer-related fatigue (CRF) is considered one of the most prevalent symptoms in brain tumor patients undergoing concurrent chemoradiation (approx. 80 % of those affected). Several studies have identified beneficial effects of physical activity on reducing CRF. However, few studies have examined the reduction of CRF by exercise in glioma patients. Here we present prospective data showing the effect of an intensive 16-week supervised exercise intervention on CRF in neuro-oncological patients. MATERIAL AND METHODS Between July 2020 and April 2023, patients with newly diagnosed glioblastoma and after surgery and concomitant radiochemotherapy have been recruited for this single-arm trial in progress. Participants have received a 16-week supervised training intervention on a 1:1-basis consisting of two intensive 50-minute sessions per week (bicycle ergometry at an average of 75 % of maximum heart rate and progressive whole-body resistance training). CRF has been assessed using the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ C30). We calculated change scores (scores: 0-100; 100=max. fatigue) from baseline, after 8 weeks, and post-intervention (week 16). RESULTS So far, 26 glioblastoma patients (13 women) aged 35-84 years (mean 59 years) participated in the exercise intervention. All patients received adjuvant chemotherapy (50 % Stupp, 42 % CeTeG, 8 % other). Paired t-test indicated a statistically significant reduction in CRF from baseline to post-intervention (p=.030; 95 % CI: -0.5 - 24.2). Mean scores reduced from 40.4 to 36.2 (week 8) to 26.9 (week 16). However, the decrease between week 0 and week 8 was not yet significant (p=.281; 95 % CI: -7.6 - 13.6). CONCLUSION The present trial shows that a 16-week supervised exercise program can reduce CRF in glioblastoma patients despite adjuvant chemotherapy. Thus, and consistent with studies of exercise interventions in patients of other tumor types, glioblastoma patients have the opportunity to actively contribute to the reduction of tumor- and therapy-induced side effects through intensive physical training.
P20.04.B DIAGNOSIS AND TREATMENT OF PERIPHERAL AND CRANIAL NERVE TUMORS WITH EXPERT RECOMMENDATIONS: AN EUROPEAN NETWORK FOR RARE CANCERS (EURACAN) INITIATIVE
Authors: A Pellerino, R Verdijk, L Nichelli, N Andratschke, A Idbaih, R Goldbrunner
Journal: Neuro-Oncology (2023)

Abstract BACKGROUND The 2021 WHO classification of the CNS Tumors identifies as “Peripheral nerve sheath tumors” (PNST) some entities with specific clinical and anatomical characteristics, histological and molecular markers, imaging findings, and aggressiveness. MATERIAL AND METHODS The Task Force has reviewed the evidence of diagnostic and therapeutic interventions, which is particularly low due to the rarity, and drawn recommendations accordingly. RESULTS Tumor diagnosis is primarily based on hematoxylin and eosin-stained sections and immunohistochemistry. Molecular analysis is not essential to establish the histological nature of these tumors, although genetic analyses on DNA extracted from PNST (neurofibromas/schwannomas) is required to diagnose mosaic forms of NF1 and SPS. MRI is the gold-standard to delineate the extension with respect to adjacent structures. Gross-total resection is the first choice, and can be curative in benign lesions; however, the extent of resection must be balanced with preservation of nerve functioning. Radiotherapy can be omitted in benign tumors after complete resection and in NF-related tumors, due to the theoretic risk of secondary malignancies in a tumor-suppressor syndrome. Systemic therapy should be considered in incomplete resected plexiform neurofibromas/MPNSTs. MEK inhibitor selumetinib can be used in NF1 children ≥2 years with inoperable/symptomatic plexiform neurofibromas, while anthracycline-based treatment is the first choice for unresectable/locally advanced/metastatic MPNST. Clinical trials on other MEK1-2 inhibitors alone or in combination with mTOR inhibitors are under investigation in plexiform neurofibromas and MPNST, respectively. CONCLUSION Given the heterogeneity and rarity of these tumors, there is a paucity of well-powered clinical trials, thus it is not possible to generate evidence-based treatment recommendations for non-surgical modalities. However, some clinical trials have been reported on targeted therapies in plexiform neurofibromas of NF1 patients or in heterogenous cohorts of soft-tissue tumors, including MPNSTs, with initial data of efficacy that need to be further investigated.